We tested the hypothesis that AMP-activated protein kinase (AMPK), an energy sensor, regulates diabetes-induced renal hypertrophy. In kidney glomerular epithelial cells, high glucose (30 mM), but not equimolar mannitol, stimulated de novo protein synthesis and induced hypertrophy in association with increased phosphorylation of eukaryotic initiation factor 4E binding protein 1 and decreased phosphorylation of eukaryotic elongation factor 2, regulatory events in mRNA translation. These high-glucose-induced changes in protein synthesis were phosphatidylinositol 3-kinase, Akt, and mammalian target of rapamycin (mTOR) dependent and transforming growth factor-beta independent. High glucose reduced AMPK alpha-subunit theronine (Thr) 172 phosphorylation, which required Akt activation. Changes in AMP and ATP content could not fully account for high-glucose-induced reductions in AMPK phosphorylation. Metformin and 5-aminoimidazole-4-carboxamide-1beta-riboside (AICAR) increased AMPK phosphorylation, inhibited high-glucose stimulation of protein synthesis, and prevented high-glucose-induced changes in phosphorylation of 4E binding protein 1 and eukaryotic elongation factor 2. Expression of kinase-inactive AMPK further increased high-glucose-induced protein synthesis. Renal hypertrophy in rats with Type 1 diabetes was associated with reduction in AMPK phosphorylation and increased mTOR activity. In diabetic rats, metformin and AICAR increased renal AMPK phosphorylation, reversed mTOR activation, and inhibited renal hypertrophy, without affecting hyperglycemia. AMPK is a newly identified regulator of renal hypertrophy in diabetes.

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Diabetic nephropathy is characterized early in its course by glomerular hypertrophy and, importantly, mesangial hypertrophy, which correlate with eventual glomerulosclerosis. The mechanism of hypertrophy, however, is not known. Gene disruption of the tumor suppressor PTEN, a negative regulator of the phosphatidylinositol 3-kinase/Akt pathway, in fruit flies and mice demonstrated its role in size control in a cell-specific manner. Here, we investigated the mechanism of mesangial hypertrophy in response to high extracellular glucose. We link early renal hypertrophy with significant reduction in PTEN expression in the streptozotocin-induced diabetic kidney cortex and glomeruli, concomitant with activation of Akt. Similarly, exposure of mesangial cells to high concentrations of glucose also decreased PTEN expression and its phosphatase activity, resulting in increased Akt activity. Expression of PTEN inhibited high-glucose-induced mesangial cell hypertrophy, and expression of dominant-negative PTEN was sufficient to induce hypertrophy. In diabetic nephropathy, the hypertrophic effect of hyperglycemia is thought to be mediated by transforming growth factor-␤ (TGF-␤). TGF-␤ significantly reduced PTEN expression in mesangial cells, with a reduction in its phosphatase activity and an increase in Akt activation. PTEN and dominant-negative Akt attenuated TGF-␤-induced hypertrophy of mesangial cells. Finally, we show that inhibition of TGF-␤ signal transduction blocks the effect of high glucose on PTEN downregulation. These data identify a novel mechanism placing PTEN as a key regulator of diabetic mesangial hypertrophy involving TGF-␤ signaling. Diabetes 55: [2115][2116][2117][2118][2119][2120][2121][2122][2123][2124][2125] 2006

Atherosclerosis is considered to be a chronic inflammatory disease characterized by enhanced expression of proinflammatory cytokines, chemokines, and adhesion molecules (1-3). The cross-talk between cytokines, chemokines, and infiltrating immune cells amplifies the inflammatory cascade in the vessel wall, resulting in atherogenesis (1-3).Interleukin-18 (IL-18) 3 is a proinflammatory and proatherogenic cytokine that induces the expression of other proinflammatory cytokines and adhesion molecules (4). IL-18 has been localized to human atherosclerotic lesions (5, 6), and circulating IL-18, which is increased in acute coronary syndromes (7), has been shown to predict future cardiovascular events (7). A positive correlation between serum IL-18 levels and carotid intima-media thickness has been demonstrated (8). Administration of IL-18 aggravates atherosclerosis in mice (9). Moreover, atherogenesis is reduced in IL-18-deficient apoE knock-out mice (10), suggesting a causal role for IL-18 in the development and progression of atherosclerosis.Recently, we demonstrated that IL-18 induces human aortic smooth muscle cell (SMC) proliferation (11). However, it is not known whether IL-18 induces SMC migration. Both migration and proliferation play a role in normal and diseased vessels (1-3). SMC migration contributes to normal angiogenesis. However, SMC migration also plays a causal role in pathological remodeling of the vessel walls during atherosclerosis, arteriosclerosis, and restenosis following angioplasty (1-3).Vessel wall remodeling is characterized by a disruption in the delicate balance between extracellular matrix (ECM) deposition and degradation, with matrix metalloproteinases (MMPs) and their inhibitors (tissue inhibitors of matrix metalloproteinases (TIMPs)) playing a prominent role. MMPs are zinc-dependent proteases and are classified as collagenases, stromelysins, elastases, and gelatinases based on substrate specificity. Their expression is regulated at both the transcriptional and post-transcriptional levels. They are synthesized as proenzymes and are activated following proteolytic cleavage. SMCs express MMP2 (gelatinase A) and MMP9 (gelatinase B), the two gelatinases described so far (12). Excess activation of MMP2 and MMP9, without alteration of TIMP expression and activation, results in destruction of the ECM and can lead to pathological remodeling and vascular restenosis (12-15). Because increased matrix degradation promotes SMC migration (15), we hypothesized that IL-18 induces SMC migration via induction of MMP9. Our novel findings demonstrate that IL-18 promotes SMC

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